HIV and methamphetamine (METH) are each associated with deleterious effects on the central nervous system (CNS). Although early evidence suggests that HIV and METH may interact to amplify neural injury via common pathways involving neuroinflammation and vasculopathy, their combined effects on the CNS remain poorly understood. To foster this line of research we propose establishing the Translational Methamphetamine AIDS Research Center (TMARC), which aims to provide scientific leadership, technical support, and opportunities for training to coalesce the efforts of an interdisciplinary group of investigators to elucidate METH/HIV-induced CNS injury. Human projects will examine inhibitory deficits (PI), dysregulated reward processing, interoception, and risk taking (P2), and the effect of HIV co-receptor tropism change on neurocognitive impairment and disease progression (P3). Animal studies will complement and extend the human studies: P4 will explore cognitive and reward effects of METH in a gp120 mouse model, while P5 will explore METH effects on a CCR5 knockout gp120 mouse model with electrophysiological, neuropathological, and neurochemical methods. A third animal project will be nested within PI to enhance translation of the human studies on inhibition to animals. Supporting these Projects will be 4 scientific Cores (Clinical Assessment and Laboratory; Neuropsychiatric; Neuroimaging; Neuroscience and Animal Models) whose activities will be synergized by an Administrative Coordinating Core that includes Units on Data Management and Information Systems, Statistics, and Participant accrual and tracking. These Cores will also serve as incubators for innovative pilot work to facilitate initiation of new studies, and will also serve as a resource by providing access to cohorts, biological samples, and data to inform future studies both by TMARC-affiliated and external investigators. TMARC will also provide opportunities for trainees to develop new research ideas on the CNS effects of HIV and drugs, thereby fostering the next generation of scientists. TMARC's ultimate vision is to become a national resource for translational multidisciplinary research and training in the neuropathogenesis of HIV and substance use.